Glioblastoma is one of the deadliest among human cancers with a highly dismal prognosis. Even with seemingly successful initial treatment, recurrence is inevitable and almost always fatal in the majority of glioblastoma cases, which implies that controlling recurrence is the key to realizing long-term survival in glioblastoma patients. A growing body of evidence now suggests that glioblastomas contain a small subpopulation of immature, undifferentiated tumor cells with tumor-initiating capacity, which is lost once they undergo differentiation. Such cells are called glioma stem cells, and due to their inherent therapy resistance, are now deemed as a possible culprit in glioblastoma recurrence. Elucidation of the molecular mechanisms underlying the maintenance of the immature, stem cell state of glioma stem cells, as well as the process of their differentiation, is therefore expected to lead to identification of novel targets of therapeutic intervention to prevent recurrence and thus could contribute to better clinical management of this devastating disease. In this review article, I will address some of the critical issues and controversies in the field of glioma stem cell research that require particular attention.

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  The Cancer Genome Atlas (TCGA), which is a multidimensional and comprehensive analyses of genomic/epigenomic alterations, has identified novel molecular changes on multiple regulatory levels (genomic, transcriptional, epigenomic) in human gliomas. The development of new technologies, such as next generation sequencing, has accelerated systematic studies of the cancer genome in recent years. Accordingly, our understanding has rapidly expanded, and some of the newly discovered molecular alterations are critical for the application of personalized medicine. These kinds of analyses have, however, also revealed the complexity of the glioma molecular basis. In this review, we will summarize these novel genetic/epigenetic insights into the nature of glioma, and further discuss its genomic complexity.

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  Since the efficacy of postoperative radiotherapy for high-grade gliomas was confirmed in the 1970s, many clinical studies have been performed to optimize dose fractionation, target volume, and concurrent therapy. Some major and drastic changes in radiation therapy over the following decades, including radiotherapy planning from 2D to 3D, use of high beam energy from gamma rays to megavoltage X-rays, and the incorporation of modern imaging modalities to radiotherapy planning, have been accompanied with a considerable improvement in outcome for this disease. However, the local control rate remains unsatisfactory even in the most recent reports, and besides, several practical considerations, such as shortening of treatment time and re-irradiation of recurrent disease, require new treatment approaches. Excellent dose distribution and accurate targeting techniques have also been established by recent progress in high precision radiation therapy, which may further contribute to improving outcomes as one of the treatment strategies.

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  The WHO grading based on a comprehensive evaluation of morphology, cell biology, genetics and immunological characteristics of primary brain tumors has been widely used as it is also a good indicator of clinical outcomes. The molecular pathology of gliomas not only serves as an adjunct to histological diagnosis but may also hold the key to developing new prognostic classifications with therapeutic implications. Despite aggressive treatment, the prognosis of malignant gliomas remains dismal. Extensive research on the genetics and epigenetics of gliomas has been carried out in order to gain a better understanding of the molecular biology of tumors. Understanding the molecular factors associated with glioma is essential for the development of an effective anti-glioma chemotherapy. Several studies report characteristic genetic factors, such as O6-methylguanine DNA-methyltransferase (MGMT), chromosome 1p19q, epidermal growth factor receptor (EGFR), TP53, and isocitrate dehydrogenase (IDH) 1 & IDH2, and suggest their potential role in the clinical prognosis of the tumor by determining the efficacy of anti-tumor chemotherapy. Reports on the major determinants of resistance to anti-glioma therapy, namely the existence of MGMT, sustained angiogenesis, and the blood-brain barrier, call for novel strategies to overcome these barriers if the fight against malignant glioma is to be won. The standard therapy for malignant gliomas is maximal resection followed by the Stupp regimen of radiation and temozolomide (TMZ) chemotherapy. TMZ, a second generation alkylating agent, has high blood-brain barrier permeability but almost half of the tumors show TMZ resistance. Various clinical trials, using TMZ as the main trunk, have tried modifying TMZ administration and combining TMZ with other anti-tumor agents in order to overcome the limits of the standard TMZ based anti-glioma therapy. Basic research and clinical trials continue to contribute to developing novel molecular-targeting agents and novel strategies to overcome the above mentioned shortcomings.
  In this paper, we review the important factors in understanding the molecular pathology of glioma and drug resistance and report on the main barriers that need to be overcome in the current standard therapy. We summarize recent clinical trials of Avastin (BEV), AVAGlio study and RTOG 0825, aimed at overcoming the barrier of angiogenesis by targeting VEGF. We also report our results on the efficacy of Interferon-β on animal models and its clinical trial—INTEGRA study. We also review the potential of local interstitial chemotherapy such as Gliadel (Carmustine, BCNU) wafers as an approach to overcome the blood-brain barrier.

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  Symptomatic radiation necrosis in the brain is a serious problem after high-dose irradiation for brain tumors. We used amino-acid positron emission tomography (PET) for the diagnosis of radiation necrosis and examined the treatment of radiation necrosis with bevacizumab, an anti-vascular endothelial growth factor antibody. In a single-institute clinical study, we administered multiple times of intravenous injection of bevacizumab, 5 mg/kg biweekly to 12 consecutive patients with symptomatic radiation necrosis in the brain, diagnosed using PET. All patients responded well to this treatment, with marked shrinkage of perilesional edema. This treatment was effective irrespective of the original tumor type and radiation modality. Based on these observations, we applied for an Investigational Medical Care System grant from Japan's Ministry of Health, Labor, and Welfare (MHLW) to study the “Intravenous administration of bevacizumab for the treatment of symptomatic radiation necrosis in the brain with the diagnosis based on amino acid PET.” The MHLW approved the grant on April 1, 2011, and the clinical trial was begun. Sixteen institutes were included and 41 cases were enrolled in this nationwide clinical trial. The final goal of the clinical trial is to determine the optimal on-label use of bevacizumab for the treatment of symptomatic radiation necrosis in the brain. We will present the results of the clinical trial in the near future.

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  In this paper, we evaluate the usefulness of 3D fusion translucent skull and venous sinus images reconstructed from CT and phase contrast MR venography. We assessed their utility in securing adequate craniotomy and skull drilling in posterior cranial fossa surgery. Translucent skull images provide detailed and accurate information about the relation of the skull structure and venous sinus. Using this imaging technique, adequate craniotomy was obtained in microvascular decompression surgery for trigeminal neuralgia and drilling of the internal auditory canal was accomplished safely in a case with a high jugular bulb. We discuss the usefulness of translucent skull and venous sinus 3D fusion images. Furthermore, it is clearly advantageous that the images can be obtained without contrast media and that the application of this imaging method can be further expanded by using various tissue information obtained from CT and MRI.

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  We experienced three patients with ataxia after stroke (ataxic hemiparesis in chronic stroke or Wallenberg syndrome in acute stroke) whose neurological deficits improved following rehabilitation using a hybrid assistive limb (HAL). All three patients had ataxia involving their limbs and/or trunk. During the HAL rehabilitation, knee flexion and stretch, sit-to-stand, and walking were all performed. HAL rehabilitation enabled them to stabilize their center of gravity. Furthermore, HAL rehabilitation shortened the time of their 10 meter walk. According to our results, we believe that HAL can be used to ameliorate the balancing and walking function in patients with ataxia after stroke.

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